The need for new, more effective, and less toxic antifungal antibiotics for the treatment of disseminated mycotic and mycobacterial infections is urgent in view of the significant toxicities and failure rates of the currently available systemic antifungal agents. The problem has become particularly relevant in view of the fact that opportunistic disseminated mycoses and atypical mycobacterial infection are common complications of Acquired Immune Deficiency Syndrome (AIDS). The discovery of new antibiotics has in the past successfully relied primarily upon the isolation of such agents from natural sources. The principal advantage of this approach over chemical synthesis or modification of existing agents is the probability of discovering new prototype drugs with quite different chemical structures and, therefore, dissimilar toxidties and cross-resistance with present drug therapies.
The discovery and extraction of an antifungal alkaloid eupolauridine from the stem and root bark of the tree Cleistopholis patens (Benth) Engl. and Diels (Annonaceae) and useful against Candida albicans is the subject of U.S. Pat. No. 4,965,272. The discovery of eupolauridine from the ethanolic extract of the root bark of the tree which is found throughout West Africa and its possibly remarkable anticandidal properties was reported in the Journal of Natural Products, Vol. 50, No. 5, pp. 961-964, Sept.-Oct. 1987 by Hufford et al. Subsequent to the discovery of eupolauridine in the ethanolic extract and its unexpected antifungal properties, the ethanolic extract was subjected to further examination using different bioassay techniques which resulted in the unexpected discovery of a new compound, 3-Methoxysampangine, and certain analogues thereof which exhibits remarkable antifungal properties against Canalida albicans, Aspergillus fumigatus, and Cryptococcus neoformans is the subject of co-pending Application Ser. No. 07/609,610. The present invention is concerned with newly discovered analogues of 3-Methoxysampangine, compositions thereof, the method of preparing the novel compounds, and the method of treatment of pathological conditions caused by fungal and mycobacterial organisms comprising administering the compound to mammals in a therapeutically-effective concentration in a non-toxic pharmaceutically-acceptable carrier.
Administration of the compound may be by any of the conventional routes of administration, for example, oral, intramuscular, intravenous, or rectally. In the preferred embodiment, the compound is administered in combination with a pharmaceutically-acceptable carrier which may be solid or liquid, dependent upon choice and route of administration. Examples of acceptable carriers include, but are not limited to, starch, dextrose, sucrose, lactose, gelatin, agar, stearic acid, magnesium stearate, acacia, and similar carriers. Examples of liquids include water, edible oils, e.g. peanut and corn.
When administered in solid form, the compound and diluent carrier may be in the form of tablets, capsules, powders, lozenges, suppositories prepared by any of the well known methods. When given as a liquid preparation, the mixture of active compound and liquid diluent carrier may be in the form of a suspension administered as such. The compound is administered in a non-toxic dosage concentration sufficient to inhibit the growth and/or destroy the Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Mycobacterium intracellulare organisms. The actual dosage unit will be determined by the well recognized factors as body weight of the patient and/or severity an& type of pathological condition the patient might be suffering with prior to becoming infected with any of the fungal organisms. With these considerations in mind, the dosage unit for a particular patient can be readily determined by the medical practitioner in accordance with the techniques known in the medical arts.